Dual Antiplatelet Therapy DAPT Duration Dilemma Recent Trials

Dual Antiplatelet Therapy (DAPT) Duration Dilemma: Recent Trials And Guidelines For Clinical Practice Dean J. Kereiakes, MD FACC FSCAI Medical Director, The Christ Hospital Heart & Vascular Center and the Lindner Research Center at The Christ Hospital, Cincinnati, Ohio Professor of Clinical Medicine, Ohio State University

Dean J. Kereiakes, MD – Disclosure Information Consulting fees: • Modest: Medpace, HCRI, Ablative Solutions, Inc. • Significant: Boston Scientific, Abbott Vascular, REVA Medical Inc.

2011 ACC/AHA/SCAI Guideline for PCI The duration of P 2 Y 12 inhibitor therapy should generally be as follows: DURATION I IIa IIb III a. In patients receiving a stent (BMS or DES) during PCI for ACS, P 2 Y 12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel 75 mg daily, prasugrel 10 mg daily or ticagrelor 90 mg twice daily I IIa IIb III b. In patients receiving DES for non-ACS indication, clopidogrel should be given for at least 12 months if patients are not at high risk for bleeding. I IIa IIb III c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless patient is at increased risk for bleeding; then it should be given for a minimum of 2 weeks) Circulation 3

Randomized Trials of DAPT Duration Trial Test Randomizat ion 1° EP 2701 DES 1 vs. 2 yrs A vs. A+C Superiority D/MI 2 yrs after rand N=20, 645 (15, 245 DES) (5, 400 BMS) N=1, 800 DES, BMS 1 vs. 2. 5 yrs* Patients Prolonged DAPT Studies REAL/ZEST Late DAPT PRODIGY 6 mos vs. 2 yrs A+P vs. DAPT D/MI/CVA (clop or pras) ST, Bleeding NI and Sup A vs. A+C D/MI/CVA Superiority Abbreviated DAPT Studies EXCELLENT ISAR-SAFE** ITALIC N=1, 443 SES and EES N=6, 000 DES 6 vs. 12 mos* N=3, 700 EES 6 vs. 12 mos N=3, 120 ZES N=2, 148 RESET‡ E-ZES vs RZES, SES, ‡Strategy not DAPT duration **2014 EES OPTIMIZE 3 vs. 12 mos A vs. A+C Noninferiority A+P vs. A+C Noninferiority D/MI/TVR D/MI/CVA/ ST/TIMI MB D/MI/CVA/ A vs. A+C Urg Noninferiority Revasc/MB A vs. A+C D/MI/CVA/M Noninferiority B CVD/MI/ST/ A+C vs. A+C ID-TVR, *Plus a 3 month washout per Bleed peri

Correlation of Clopidogrel Therapy Discontinuation in REAL-world Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events: REAL-LATE Trial Patients on current dual antiplatelet therapy without MACCE or major bleeding for at least the first 12 months after DES implantation (Total N~2, 700) Aspirin + clopidogrel Dual-therapy (N=1, 000) 1: 1 randomization Stratified by (1) centers (2) Initial DES types Aspirin Mono-therapy (N=1, 000) Regular Clinical assessment after randomization Primary end points: The composite of cardiac death or MI

PRODIGY Study: 6 vs 24 m DAPT after DES or BMS, randomized at 30 days 2, 013 randomly allocated to recieve one of the four study stent types 499 randomized to and received EES 498 randomized to and received PES 500 randomized to and received ZES 502 randomized to and received BMS (1497 DES) 694 Excluded, 353 Not Meeting Inclusion Criteria 232 Refused to Participate, 109 Operator’s choice 1, 970 DES and BMS randomized at 30 days 983 BMS 30 d treatment allowed and counted as 6 m 6 Months DAPT Ff 984 f 2 year follow-up Not blinded Primary EP Death, MI, CVA 987 24 Months DAPT Ff 979 f 2 year follow-up Valgimigli, M. , et al. , Circulation, 2012.

EXCELLENT Trial Design Prospective, open label, two-arm, randomized multi-center trial 1372 Patients Matching Enrollment Criteria 19 centers in Korea Everolimus-Eluting Stent N=1029 DAT 6 mo DAT 12 mo N=515 N=514 Randomization 3: 1 Sirolimus-Eluting Stent 2 x 2 factorial design DAT 6 mo DAT 12 mo N=171 N=172 N=343 Percutaneous Coronary Intervention clinical endpoint evaluation Clinical 1 mo Angiographic *CD, MI, IDTVR 3 mo 9 mo 12 mo Primary endpoint: In-segment LL TVF* 2 yr 3 yr 4 yr 5 yr Am Heart J 2009 May; 157: 811 -817 Gwon et al. Circ. 2012; 125: 505 -51 7

OPTIMIZE STUDY 3, 120 minimally selected* patients undergoing PCI with E-ZES in 33 sites in Brazil Randomization ** (1: 1) DAPT for 3 months N = 1, 560 DAPT for 12 months N= 1, 560 Clinical FU at 1, 3, 6, 12 and 18 months and yearly up to 3 yrs Primary endpoint: Net Clinical Benefit † at 12 -month FU Feres et al. AHJ 2012: 164: 810 Feres et al. TCT 2013 LBCT * Exclude ACS with + biomarker; prior DES Rx; SVG target ** Stratified by DM and Institution; not blinded † composite endpoint of all-cause death, MI, CVA and major bleeding

Ischemic Endpoints By DAPT Duration In Randomizedtt Trials t EXCELLENT PRODIGY OPTIMIZE tttt 12 % Patients 10 ttt ZEST-LATE 6 mos (n=957) 6 mos (n=1546) 12 mos (n=1344) mos (n=1563) 10. 1 12 mos (n=970) 9. 6 24 10 mos (n=1500) 24 mos (n=1357) mos (n=1556) 8. 9 8. 4 7. 5 8 6 REAL-LATE/ 3 12 8. 4 7. 5 4. 7 4. 4 4. 6 4 4. 1 3. 2 1. 7 2 2. 3 1. 8 0 TVF* MACCE** *Cardiac death / MI / TVR **Death / MI, CVA, Revasc ***Death/MI/Revasc D/MI/CVA Adapted from Cardiac D/MI MACE*** t Gwon et al. ACC 2011 tt Valgimigli et al. ESC 2011 ttt Park et al. NEJM

Major Bleeding (TIMI or GUSTO/REPLACE 2* ) By DAPT Duration In Randomized Trials EXCELLENT t * OPTIMIZE tttt 3 % Patients 2. 5 6 mos 12 mos PRODIGY tt 6 mos REAL-LATE/ ttt ZEST-LATE 12 mos 24 mos P=0. 42 P=0. 04 2 3 24 mos P=0. 35 12 P=0. 66 1. 5 1 0. 5 0. 6 0. 7 0. 6 0. 3 0. 1 0 0. 8 0. 2 Adapted from t Gwon et al. ACC 2011 tt Valgimigli et al. ESC 2011 ttt Park et al. NEJM

Type II, III or V BARC Bleeding: PRODIGY CEC adjudicated 12 24 mo DAPT 6 mo DAPT P=0. 0001 8 7. 4 % 8 4 3. 5 Hazard ratio: 0. 46 (0. 1 -0. 69) 0 0 180 360 540 720 No. at Risk 24 -month clopidogrel 987 925 884 6 -month clopidogrel 983 919 881 Valgimigli et al. Circulation 2012; 125: 2015 -2026

10 PRODIGY BARC Bleeding Categories 24 mo DAPT 6 mo DAPT 8 % 6 4 P=0. 001 P=0. 075 4. 0 P=0. 029 2. 5 2 1. 5 1. 4 0. 9 0. 5 0 BARC 2* BARC 3 BARC 5 *BARC 2 “Any overt, actionable sign of hemorrhage that…meets at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation…no change in hemoglobin, blood transfusion or hemodynamic sequelae are required” Mehran et al. Circ 2011; 123: 2736 -2747

OPTIMIZE : NACCE at 1 Year (All-Cause Death, MI, Stroke, Major Bleeding) Cumulative Incidence of NACCE (%) 15 3 M DAPT 12 M DAPT Log-Rank P = 0. 838 10 6. 0 5. 8 5 0 3 6 9 Time After Initial Procedure (Months) 0 12 No. at risk 3 M DAPT 12 M DAPT 1563 1556 1520 1514 1504 1497 1468 1466 1384 1381 Feres et al. TCT 2013 LBCT

Primary Endpoint: NACCE at 1 Year (All-Cause Death, MI, Stroke, Major Bleeding) 3 M DAPT (N = 1563) 6. 1% 12 M DAPT (N = 1556) 5. 9% Difference Upper 1 -sided 95% CI : 0. 2% Non-inferiority P value : 2. 0% = 0. 002 Zone of non-inferiority Pre-specified margin = 2. 7% Non-inferior -1. 0 -0. 5 0. 0 0. 5 1. 0 1. 5 2. 0 2. 5 3. 0 3. 5 4. 0 % Upper one-sided 95% CI Primary Non-Inferiority Endpoint Met

OPTIMIZE : Other Clinical Events at 1 Year* 3 Months DAPT (N = 1563) 12 10 12 Months DAPT (N = 1556) Ischemic / Efficacy 12% 8. 4 Events (%) 8 Bleedi ng / Safety 7. 5 12% 6 14% 4 3. 2 4. 6 9. 4% 4. 1 2. 8 3. 5 3. 2 2 12. 5% 0. 7 0. 8 0 MACE MI *All P=NS Cardiac Death/MI TLR Major Bleed Feres et al. TCT 2013 LBCT

OPTIMIZE: Stent Thrombosis* vs. Major Bleeding ARC Def. /Prob. Stent Thrombosis Cumulative Incidence (%) 3 M DAPT 12 M DAPT P = 0. 64 HR 0. 81 (0. 34 -1. 96) P = 0. 18 HR 3. 97 (0. 44 -35. 49) 5 ~4 x 0 0. 7 0. 6 0 3 6 9 0. 26 0. 07 12 Time After Initial Procedure (months) Cumulative Incidence (%) 10 10 3 M DAPT 12 M DAPT 5 P = 0. 79 HR 0. 87 (0. 32 -2. 40) P = 0. 31 HR 0. 50 (0. 12 -1. 99) 2 x 0. 4 0. 2 0 0 3 6 9 12 Time After Initial Procedure (months) Feres et al. TCT 2013 LBCT *0. 2% absolute difference

RESET 2, 148 patients enrolled and randomized E-ZES with 3 -month DAPT Divided into 4 subsets and 1: 1 Standard Therapy randomization was performed Other DES with 12 -month DAPT 31 patients excluded - 16 withdrawal of consent - 15 Met exclusion criteria E-ZES with 3 -month DAPT (N=1059) Diabetes mellitus Subset (N=292) E-ZES (N=146) Primary Acute coronary syndrome Subset (N=601) R-ZES E-ZES (N=146 (N=301 Endpoint: ) ) R-ZES (N=300) CV death, MI, ST, ID-TVR, Bleed (TIMI major Standard therapy (N=1058) Short-length DES Subset (N=681) E-ZES (N=341 ) Long-length DES Subset (N=543) SES E-ZES EES (N=340 (N=271 (N=272) ) ) Kim et al. JACC 2012; 60: 1340 -1348

RESET: Clinical Events Through 1 Year % Patients Adapted from Kim et al. JACC 2012 Sep 5 (e-Pub ahead of print) 40 2 41 8 11 2 3 6 *Primary Endpoint: (Assumed 10% with N. I. margin 4% for absolute difference in risk)

ISAR-SAFE 5 1 Study Flowchart -8 th to Drug- Eluting Stenting -5 th s i s 0 2 Continuous Clopidogrel therapy for 5 to 8 months Placebo for 6 months 1 st 6 th 9 th y l a Randomization 0 y r a m i r n A Clopidogrel 75 mg/d for 6 months Follow Up 1 st FU: 1 month after randomization 2 nd FU: 6 months after randomization (at least one day after study drug cessation) 3 rd FU: 9 months after randomization (at least 3 months after study drug cessation) P PEP = death, MI, stent thrombosis, stroke, TIMI major bleed

DAPT: Study Design Eligible for Enrollment after PCI • Any PCI with DES or BMS • >18 years of age • No contradictions to dual antiplatelet therapy • Able and willing to provide written informed consent n A y l a Eligible for Randomization at 12 m Stratified by DES v BMS, drug type, and complexity (ACS or lesion-based) y r a m i r 18 12 m DAPT Arm 30 m DAPT Arm mo s Aspirin + blinded placebo Aspirin + blinded thienopyridine P Study treatment period 12 -30 m Study observation period 30 -33 m s i s 4 1 0 2 Not Eligible for Randomization at 12 m • Death • MI or repeat PCI at > 6 weeks • CABG • Stroke • Major Bleed Total 33 month follow-up Primary analysis DES treated subjects, 12 -30 m Secondary analysis propensity matched BMS to DES subjects 0 -30 m 2 co-primary endpoints: stent thrombosis and MACCE (death, myocardial infarction or stroke) Powered safety endpoint: major bleeding (GUSTO) Total 33 month follow-up Mauri, Kereiakes et al AHJ 2010; 160: 1038 -10 20

Thienopyridine Type: DAPT Study All Randomized Subjects; N = 11, 649 32 68 Clopidogrel Prasugrel

Stent Type: DAPT Study All Randomized Subjects N = 11, 649 DES Type* N= 9, 961 14 86 DES BMS Cypher (n=1, 196) Endeavor (n=1, 310) TAXUS (n=2, 786) Xience/PROMU 12. 0% 13. 1% 28. 0% *Some patients received more 48. 9% than one DES type S (n=4, 874)

Complexity Amongst Randomized Subjects: DAPT *clinical =ACS, renal insufficiency LVEF <30% **anatomic=UPLM; >3 vessels; >2 lesions/vessel; LL ≥ 30 mm; bifurcation; DES ISR; SVG;

Cumulative incidence rate (%) EXCELLENT Trial: Target Vessel Failure 6 -mo DAT 12 -mo DAT P=0. 507 HR = 1. 17 (95% CI 0. 73 -1. 89) 4. 7% 4. 4% Months after initial procedure Patient Number at Risks 6 -month 722 707 701 697 681 12 -month 721 710 699 698 680 Am Heart J 2009 May; 157: 811 -81

TVF According To Diabetes And DAPT Duration: EXCELLENT Non-diabetics Diabetics p=0. 022 HR = 0. 42 (95% CI 0. 20 -0. 88) 6 -mo DAT 12 -mo DAT p=0. 005 8. 8% HR = 3. 15 (95% CI 1. 41 -7. 01) 5. 2% 2. 9% 2. 2% Patient Number at Risk 6 -mo 450 446 445 443 437 272 261 259 255 245 12 -mo 443 435 432 429 416 278 275 271 270 265 Gwon et al, ACC 2011 LBCT

6 vs. 12 months DAPT After DES: EXCELLENT Total Age <65 ACS 767 6 mo DAPT n (%) 12 mo DAPT n (%) 19 (5. 1) 12 (3. 2) HR (95% CI) P value 1. 61 (0. 783. 31) 0. 20 0. 19 ≥ 65 676 15 (4. 5) 18 (5. 5) 0. 83 (0. 421. 65) 0. 59 No 699 21 (6. 03) 13 (3. 82) 1. 61 (0. 8 -3. 21) 0. 18 0. 15 Yes 744 13 (3. 65) 17 (4. 69) 0. 78 (0. 381. 60) 0. 50 Diabetes No 893 10 (2. 27) 22 (5. 08) 0. 44 (0. 210. 94) 0. 03 550 24 (9. 09) 8 (2. 96) 3. 16 (1. 427. 03) 0. 005 1097 26 (4. 91) 24 (4. 42) 1. 12 (0. 641. 95) 0. 69 2 (3. 08) 4 (7. 41) 0. 41 (0. 072. 23) 0. 30 Yes LVEF ≥ 50% <50% 124 Stent type Gwon et al. Circulation 2012; 125: 505 -13 Interacti on P-value <0. 001 0. 27 0. 125 0. 5 1 Favors 6 mo DAPT 2 4 8 Favors 12 mo D

Clopidogrel Duration after PCI in Diabetics*: Death and Non-Fatal Myocardial Infarction < 6 months 6 -9 months Cumulative Incidence (%) Composite of death & MI p <0. 001 0 90 # at risk < 6 mos 261 6 - 9 mos 117 > 9 mos 371 Death p < 0. 001 180 270 360 450 540 630 Time (days) 234 113 358 222 106 356 > 9 months 0 174 83 286 *749 consecutive diabetic patients/Kaiser L. A. 90 180 270 360 450 Time (days) 261 117 371 239 116 362 540 630 231 111 361 Brar et al. JACC 2008; 51: 22

Stent Type and Clopidogrel Duration After PCI in Diabetics: Death and Non-Fatal Myocardial Infarction w/ clopidogrel w/o clopidogrel DES Cumulative Incidence (%) BMS 0 landmark-left censored P=0. 01 P=0. 07 90 180 270 360 450 540 630 Time (days) # at risk BMS with clop 147 BMS w/o clop 74 145 67 139 64 0 90 180 # at risk DES with clop DES w/o clop 270 360 450 Time (days) 323 127 540 312 125 630 220 83 Brar et al. JACC 2008; 51: 2220

Multivariate Analysis Predictors of BARC Bleeding Events on DAPT* OR (95% CI) P Female 2. 7 (1. 84. 1) <0. 00 1 Non-diabetic 1. 9 (1. 23. 1) 0. 005 VLTPR (VASP≤ 10%) 4. 7 (2. 78. 3) <0. 00 1 -2 1 2 4 10 6 8 *1, 542 patients (clopidogrel 1155; prasugrel 387) Adapted from Cuissett et al. JACC Card Int

Stent Thrombosis Stratified by Clinical Syndrome and Stent Type Definite Stent Thrombosis (%) BMS: SA vs. ACS logrank p=0. 01 DES: SA vs. ACS logrank p=0. 0007 0 24 SA: BMS vs. DES logrank p=0. 2 ACS: BMS vs. DES logrank p=0. 06 ACS vs SA logrank p<0. 0001 DES, ACS BMS, ACS DES, SA SA 6 30 12 36 18 24 Time (months) N=5, 816 BMS, SA 30 36 0 6 12 18 Time (months) Kukreja et al. JACC Intv 2009; 2: 53

Analysis of DAPT Duration Beyond 1 Year Following PCI for AMI*: COREA-AMI Registry % Patients Death, NFMI, Stroke 25. 0 20. 0 18. 0 P<0. 001 for trend 15. 0 10. 2 10. 0 8. 9 5. 0 0. 0 12 -18 months 18 -24 months >24 months *2293 consecutive patients MACCE + major bleed free at 1 year post-MI Koh et al. JACC 2013; 61: A 40 (abstract E 161; presentation

Cumulative mortality rate Mortality Following PCI for ACS by Clopidogrel Use: Veterans Administration 2003 -2004* Off clopidogrel On clopidogrel Follow-up time, days *n=1455 (66% BMS, 34% DES) HR BMS 2. 65; DES 2. 0 Ho et al. Am Heart J

Freedom from Cardiac Death, M I and Revasc Target And Non-target Lesion MACE* After Stenting In 1, 057 Patients (Sirius Trial) % Vessel Target Vessel Non-target % 74. 3 % 72. 3 % SES BMS p<0. 001 57. 1 % SES BMS Log-Rank 0 360 720 1080 1440 1880 Time after Initial Procedure (days) *CV Death, M I, Revasc 74. 2 % Log-Rank p=0. 096 0 360 720 Time after Initial Chacko, Cutlip et al.

CHARISMA: Dual Therapy Vs. ASA Monotherapy In Symptomatic* Patients CD / MI / Stroke *Prior MI, CVA or symptomatic PAD Bhatt et al. JACC 2007; 49: 1982 -1988

Failure rate Death / MI Events Following Clopidogrel Discontinuation After SVG PCI Sachdeva et al. JACC 2012; Oct 25 [Epub ahead

Cumulative incidence of D / MI / CVA (%) Stenting for ISR: PRODIGY Substudy 0. 85 short DAPT regimen (n=114) long DAPT regimen (n=110) 0. 90 0. 95 P=0. 034 1. 00 0 60 120 180 240 300 360 420 480 540 600 660 720 Time (days) Campo et al. JACC 2013 prepu

Definite Stent Thrombosis Through 3 Years In 18, 334 Patients (28, 739 Lesions) By Stent Type BMS 1 G-DES 2 G-DES Stent Thrombosis (%) Stent thrombosis (%) 3 -Year Incidence of Stent Thrombosis Landmark Analysis 1 -Year BMS 1 G-DES 2 G-DES Tada, Kastrati et al. JACC INTV 2013;

Clinical Outcomes By Statistical Model, Duration of DAPT And Follow-Up: Meta Analysis of 13 RCCT Involving 17, 097 Patients TVR Stent Thrombosis MI Statistical Model Random (13) Fixed (13) Clopidogrel Duration 6 months (5) 12 months (7) Follow-up Duration ≤ 1 year (12) . 1 > 1 year. Favors (7) 4 EES Non-EES 1 10 Non-EES 0. 4 EES 4 Non-EES 0. 4 EES Baber et al. JACC 2011; 58: 569 -77

Control Long-term Risk Of Def/Prob Stent Thrombosis: Network Meta-Analysis Of 76 Treatment. RCCT* Control Odds 95% Ratio Cr. I BMS (Ref) Sirolimus Paclitaxel Everolimus Zotarolimus -R 0. 80 1. 11 0. 46 0. 69 0. 62 0. 61 0. 85 0. 31 0. 39 0. 29 1. 10 1. 49 0. 70 1. 28 1. 44 Paclitaxel Everolimus Zotarolimus -R 1. 38 0. 57 0. 87 0. 78 1. 02 0. 39 0. 48 0. 35 1. 84 0. 84 1. 50 1. 73 Everolimus Zotarolimus -R 0. 41 0. 62 0. 56 0. 29 0. 35 0. 26 0. 60 1. 11 1. 25 1. 52 0. 77 2. 83 2. 71 Sirolimus (Ref) Paclitaxel (Ref) Everolimus (Ref) * >86% Zotarolimus 0. 10 probability that EES 10. 0 has Zotarolimus 1. 0 lowest rate of “any” stent Bangalore 1. 36 et al. Circ 0. 68

Network Meta-Analysis of 49 Trials Involving 50, 844 Patients ds rtio (95% CI) 0. 42 (0. 170. 95) Late definite or probable thrombosis Co. Cr-EES vs BMS Co. Cr-EES vs 0. 33 (0. 150. 71) Co. Cr-EES vs R- 0. 24 (0. 050. 94) E- 0. 19 (0. 040. 75) PES ZES Co. Cr-EES vs ZES SES vs PES PC-ZES vs SES Favors stent 1 0. 01 stent 2 0. 1 100 1 Favors 0. 41 (0. 170. 90) 4. 31 (1. 0819. 05) 10 Palmerini et al. Lancet 2012; 379: 1393 -1402

DAPT Duration: Conclusions 1. “One size shoe” approach for DAPT duration is unlikely to fit all patients ACS • Diabetes • CABG-SVG / ISR • We treat symptomatic patients and non-target lesions with objective to reduce events (D/MI/CVA) which may not be stent (target lesion) related 3. Stent platforms differ with respect to risk for early , late and/or very late stent thrombosis events (“All DES not created equal”) 4. Conclusions regarding “optimal” DAPT duration 2.

Stent Thrombosis and DAPT Interruption Through 2 Years: Pooled Analysis of SPIRIT II-V; WOMEN; XV USA/India Analysis population 11, 219 / 13, 259 (84. 6%) pts complete DAPT data to 2 years 85 events in 83 pts (0. 74%) through 2 years 45 ST events occurred in 44 pts with no DAPT interruption from day 1 through 2 yrs 40 ST events occurred in 39 pts with some DAPT interruption from day 1 though 2 yrs 45 events occurred “On” DAPT* 23 events occurred “On” DAPT 17 events occurred “Off” DAPT ► 68/85 ST events (80. 0%) occurred “On” DAPT *One patient did not receive loading lose and was off DAPT at ST event (day 0) but started day 1 and never interrupted through 730 days. Stone et al. JACC 2011; 58(Suppl B): 78